Targeting complement 5a-mediated immunoregulation for neurofibroma therapy

靶向补体 5a 介导的免疫调节用于神经纤维瘤治疗

基本信息

批准号：
9807327
负责人：
NANCY RATNER
金额：
$ 39.75万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9807327
关键词：
Affect Apoptosis Benign Biological Assay Biological Models Biology Body Weight decreased C5AR2 gene C5a anaphylatoxin receptor Cell Death Cell Proliferation Child Clinical Trials Complement 5a Complement Activation Data Disease Dose Drug Kinetics Enzyme-Linked Immunosorbent Assay Excision Gene Proteins Genetic Complementation Test Genetic Engineering Growth Human Image Immune Immunohistochemistry Immunologic Monitoring Individual Inflammation Inflammatory Inherited Injections Legal patent Letters MEK inhibition MEKs Magnetic Resonance Imaging Malignant Neoplasms Maximum Tolerated Dose Measurement Measures Mediating Monitor Mus Nerve Neurofibromatoses Neurofibromatosis 1 Pathway interactions Patients Peptides Peripheral Nerves Peripheral Nervous System Neoplasms Pharmaceutical Preparations Pharmacodynamics Phase Phase I Clinical Trials Plasma Plexiform Neurofibroma Preclinical Testing Principal Investigator Property Retreatment Testing Therapeutic Effect Time Tissues Toxic effect Toxicology Tumor Burden Tumor Volume Tumor-infiltrating immune cells Work base complement system cytokine experience immunoregulation in vivo inhibitor/antagonist intraperitoneal mouse model multidisciplinary neoplastic cell neurofibroma off-patent partial response pharmacokinetics and pharmacodynamics phase 1 testing predictive modeling programs response subcutaneous success therapeutic evaluation therapeutic target treatment duration treatment effect tumor

项目摘要

Principal Investigator/Program Director (Last, first, middle): Wu, Jianqiang/Ratner, Nancy Abstract Neurofibromatosis type 1 (NF1) is a common inherited human disorder affecting about 1:2500 individuals worldwide. About half of NF1 patients develop plexiform neurofibromas, benign but devastating peripheral nerve tumors; surgical removal is often impossible due to the integration of tumor in critical peripheral nerves. We found that MEK inhibition shrinks 70% of tumors in DhhCre;Nf1fl/fl neurofibroma-bearing mice. This result in a mouse model predicted success of a phase I/II clinical trial for children with NF1 and large inoperable plexiform neurofibroma, in which MEK inhibition using Selumetinib in showed unprecedented activity, with 70% of patients experiencing sustained partial responses. However, the maximal tumor volume decrease was 50%, and continued MEK inhibition was required for sustained response. Therefore, we searched for genes, proteins, and pathways that are not normalized by MEK inhibition. Based on our promising preliminary data, we will test the therapeutic effects of targeting the one of these, the C5a/C5aR pathway in plexiform neurofibroma. The work proposed in this application will test if C5a is a therapeutic target for plexiform neurofibromas, alone or in combination with MEK inhibition. We will measure PK and PD, and efficacy. Our multidisciplinary team includes world leaders in neurofibroma preclinical testing, an expert in volumetric measurement for neurofibroma, a biostatistician, and experts in the biology of the complement system who developed unique antagonists of C5aR, and NF1 clinicians.

首席研究员/项目总监（后、一、中）：吴建强/Ratner, Nancy 抽象的 1 型神经纤维瘤病 (NF1) 是一种常见的遗传性人类疾病，影响约 1:2500 世界各地的个人。大约一半的 NF1 患者会出现丛状神经纤维瘤，虽然是良性的，但毁灭性的周围神经肿瘤；由于整合，手术切除通常是不可能的关键周围神经的肿瘤。我们发现 MEK 抑制使 70% 的肿瘤缩小 DhhCre；Nf1fl/fl 携带神经纤维瘤的小鼠。这一结果在小鼠模型中预测了针对 NF1 儿童和不可手术的大型丛状神经纤维瘤的 I/II 期临床试验，其中使用 Selumetinib 抑制 MEK 表现出前所未有的活性，70% 的患者经历持续的部分反应。然而，最大肿瘤体积减少了50%，持续的反应需要持续的 MEK 抑制。因此，我们寻找 MEK 抑制未使基因、蛋白质和途径正常化。基于我们的承诺初步数据，我们将测试针对其中之一 C5a/C5aR 的治疗效果丛状神经纤维瘤中的通路。本申请中提出的工作将测试 C5a 是否是丛状神经纤维瘤的治疗靶点，单独或与 MEK 抑制联合使用。我们将测量 PK 和 PD 以及疗效。我们的多学科团队包括神经纤维瘤领域的世界领先者临床前测试，神经纤维瘤体积测量专家，生物统计学家，补体系统生物学专家，开发了独特的 C5aR 拮抗剂，以及 NF1 临床医生。